Human Drug Testing Phase I: Determining the Maximum Tolerated Dose

The first step (Phase I) in human drug testing is to determine how much drug you can safely give to a person, which scientists express in more-precisely defined terms:

Dose-limiting toxicities (DLTs) are unacceptable side effects that would force the treatment to stop (or continue at a reduced dose). The term unacceptable is relative; severe nausea and vomiting would probably be considered unacceptable (and therefore DLTs) for a headache remedy, but not for a chemotherapy drug. For each drug, a group of experts decides what reactions constitute a DLT.

The maximum tolerated dose (MTD) is the largest dose that doesn’t produce DLTs in a substantial number of subjects (say, more than 5 or 10 percent of them).

An old saying (six centuries old, in fact) is that “dose makes the poison.” This adage means that everything is safe in low enough doses (you can fearlessly swallow one microgram of pure potassium cyanide), but anything can be lethal in sufficiently large doses (drinking a gallon of pure water in an hour may well kill you).

The goal of a Phase I trial is to determine the drug’s MTD, which will mark the upper end of the range of doses that will be allowed in all subsequent trials of this drug. A typical Phase I trial enrolls subjects into successive groups (cohorts) of about eight subjects each.

The first cohort gets the drug at one particular dose and its subjects are then watched to see whether they experience any DLTs. If not, then the next cohort is given a larger dose (perhaps 50 percent larger or twice as large). This dose-escalation process continues as long as no DLTs are seen.

As soon as one or more DLTs occur in a cohort, the area around that dose level is explored in more detail in an attempt to nail down the best estimate of the MTD. Depending on how many DLTs are observed at a particular dose level, the protocol may specify testing another cohort at the same dose, at the previous (lower) dose level, or somewhere in between.

Phase I trials are usually done on healthy volunteers because they’re mainly about safety. An exception is trials of cancer chemotherapy agents, which have so many unpleasant effects (many of them can actually cause cancer) that it’s usually unethical to give them to healthy subjects.

A drug may undergo several Phase I trials. Many drugs are meant to be taken more than once — either as a finite course of treatment (as for chemotherapy) or as an ongoing treatment (as for high blood pressure). The first Phase I trial usually involves a single dosing; others may involve repetitive dosing patterns that reflect how the drug will actually be administered to patients.

The statistical analysis of Phase I data is usually simple, with little more than descriptive summary tables and graphs of event rates at each dose level. Usually, no hypotheses are involved, so no statistical testing is required. Sample sizes for Phase I studies are usually based on prior experience with similar kinds of drugs, not on formal power calculations.

The dose level for the first cohort is usually some small fraction of the lowest dose that causes toxicity in animals. You might guess that tolerable drug doses should be proportional to the weight of the animal, so if a 5-kilogram monkey can tolerate 30 milligrams of a drug, a 50-kilogram human should tolerate 300 milligrams.

But tolerable doses often don’t scale up in such a simple, proportionate way, so researchers often cut the scaled-up dose estimate down by a factor of 10 or more to get a safe starting dose for human trials.

Even with these precautions, the first cohort is always at extra risk, simply because you’re sailing in uncharted waters. Besides the possibility of nonproportional scale-up, there’s the additional danger of a totally unforeseen serious reaction to the drug.

Some drugs (especially antibody drugs) that were perfectly well tolerated in rats, dogs, and monkeys have triggered severe (even fatal) reactions in humans at conservatively scaled-up doses that were thought to be completely safe. So extra precautions are usually put in place for these “first in man” studies.

Besides the primary goal of establishing the MTD for the drug, a Phase I study almost always has some secondary goals as well. After all, if you go to the trouble of getting 50 subjects, giving them the drug, and keeping them under close scrutiny for a day or two afterward, why not take advantage of the opportunity to gather a little more data about how the drug behaves in humans?

With a few extra blood draws, urine collections, and a stool specimen or two, you can get a pretty good idea of the drug’s basic pharmacokinetics:

How fast it’s absorbed into the bloodstream (if it’s taken orally)

How fast (and by what route) it’s eliminated from the body

And, of course, you don’t want to pass up the chance to see whether the drug shows any signs of efficacy (no matter how slight).